71. Overview. a. Comments received. FDA received a considerable number of comments concerning the proposed reporting of adverse drug experiences of marketed drugs, especially the time frames for such reporting. The current regulations base the reporting times on whether the adverse drug experience is expected or unexpected. All "unexpected" adverse drug experiences are required to be reported within 15 working days, and all "expected" adverse drug experiences are required to be reported in the next periodic report (quarterly in the first year following approval, semiannually in the second year, and annually thereafter). The proposal (with one exception) would have created a standard time frame of 30 working days for reporting almost all kinds of adverse reactions -- serious, nonserious, expected, and unexpected. The one exception was a proposed 15-day alert report for fatal and life-threatening adverse drug experiences not mentioned in the product's approved labeling.

The primary criticism of the proposal made by the comments was that, except for the limited 15-day report, the proposal failed to distinguish the more important adverse drug experiences from the less significant ones. Without such focus, the comments argued, the public health would not be best served because both the agency and the pharmaceutical companies would be spending a disproportionate amount of time processing trivial, known reactions -- time that could be better spent evaluating and following up on serious adverse drug experiences that are more likely to affect the public health. Comments also complained that, unlike current regulations, the proposal did not make the reporting requirements less frequent for known and nonserious experiences once the drug had been on the market for a period of time.

Given all of these factors, FDA has reevaluated the objectives of the adverse drug reporting system and the regulatory requirements most appropriate to implement them. Based on this review, the agency has modified the final rule in a number of ways designed to increase the system's efficiency and thereby improve public health protection. The details of these modifications are stated below, following a description of the objectives of the reporting system.

b. Objectives of the reporting system. Although premarket testing discloses a general safety profile of a new drug's comparatively common adverse effects, the much larger patient population and longer period of use associated with the marketing of a drug provides, for the first time, the opportunity to collect information on rare, latent, and long-term effects, some of which may be serious. Accordingly, the primary objective of the adverse drug experience reporting system is to signal potential serious safety problems with marketed drugs, especially newly marketed drugs. As described below, a signal may be received in a variety of ways. Receipt of the initial signal triggers considerable followup work and analysis before any conclusion about necessary action can be reached (e.g., a "Dear Doctor" letter, revised labeling, or, in rare cases, market withdrawal). Thus, the agency believes that the goal of any regulations in this area should be to direct attention to those reports most likely to contain information on potentially serious safety problems.

c. The final rule. The final rule has been modified in the following ways so that the reporting requirements are tailored to signal potentially serious, new information.

(1) Requirement for 15-day Alert reports. Under the final rule, all adverse drug experiences that are both "serious and unexpected," and any "significant increase in frequency" of an adverse drug experience that is both "serious and expected," will be required to be reported to FDA as soon as possible, but in any case within 15 working days. These are the adverse drug experiences most likely to reveal serious safety problems that were not revealed during the clinical trials and which, therefore, are likely to necessitate a labeling change or other action to protect the public health. FDA believes that the broadening of the 15-day reporting requirement from that in the proposal, which would have required that only unexpected fatal and life-threatening experiences be reported, will increase public health protection. Throughout the final rule, references to "15-day Alert reports" (unless specified otherwise) refer to reports of "serious and unexpected" adverse drug experiences as well as reports of a "significant increase in frequency" of a serious, expected adverse drug experience.

The final rule defines both "serious" and "unexpected" in order to clarify the 15-day reporting requirement. Both of these definitions have been adopted from a draft guideline that has been made available for public comment (see 48 FR 4049; January 28, 1983).

For purposes of the final rule, the term "serious" means an adverse drug experience that is life threatening, is permanently disabling, requires in patient hospitalization, or requires prescription drug therapy. In addition, an adverse drug experience that results in death, congenital anomaly, cancer, or overdose is always to be considered serious.

The term "unexpected" means an adverse drug experience that is not listed in the current labeling for the drug and includes an event that may be symptomatically and pathophysiologically related to an event listed in the labeling, but differs from the event because of greater severity or specificity. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the labeling only referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the labeling listed only cerebral vascular accidents. This definition of "unexpected" is based on an evaluation of individual case reports of an adverse drug experience.

The regulation also defines "increased frequency," which is defined to mean an "absolute increase in the number of reports of an adverse drug experience received during a specified time period compared to the number of similar adverse drug experience reports received during an equivalent time period in the past." In contrast to the definition of "unexpected," the definition of "increased frequency" is necessarily based on an analysis of a series of previous adverse drug experience reports, rather than a single report.

The 15-day reporting requirement will apply to any "significant" increase in frequency of a serious, expected adverse drug experience. In order to meet this requirement, applicants are required to review periodically the frequency of reports of "serious" adverse drug experiences that are "expected." The regulation requires applicants to conduct this periodic review at least as often as the periodic reporting cycle, and FDA will provide written notice to applicants when the agency believes that circumstances warrant more frequent periodic review (e.g., approval of a major new indication or where previous reports signal possible safety problems with the drug). FDA will describe in a guideline the factors which would make an increased frequency "significant" so as to trigger the 15-day reporting requirement, including an increased "rate of occurrence" of the adverse drug experience based on some measure of use of the drug (such as total prescriptions). Given this periodic review and analysis, the final rule requires applicants to report to FDA any significant increase in frequency of a serious, expected adverse drug experience as soon as possible but in any case within 15-working days of determining that a significant increase in frequency exists. Of course, if an applicant receives a large number of reports within a short period of time, so that a significant increase in frequency is readily apparent, a 15-day Alert report would be required at that juncture.

(2) Format for 15-day Alert reports. The final rule specifies the format for submission of 15-day Alert reports. This format differs, depending upon whether the report is based on a single "serios and unexpected" adverse drug experience or on a "significant increase in frequency" of a serious, expected adverse drug experience (i.e., a series of events). The final rule requires reports of "serious and unexpected" adverse drug experiences to be submitted on Form FDA-1639 because that form is designed to contain information on individual adverse drug experiences. In contrast, the final rule requires applicants to submit reports of significant increases in frequency in narrative form (including the time period on which the increased frequency is based, the method of analysis, and the interpretation of results) rather than using Form FDA-1639. This is because Form FDA-1639 is not well suited for reporting a group of adverse drug experiences. As stated below, however, the requirement for periodic reports requires that a Form FDA-1639 for each "serious and expected" (as well as "nonserious") adverse drug experience be included in each periodic report. Finally, in order to facilitate expedited processing by the agency, the final rule requires prominent identification of all 15-day Alert reports.

(3) Requirement for periodic reports. For all other adverse drug experiences, the final rule requires periodic reporting at quarterly intervals for the first 3 years following approval, and at annual intervals thereafter. This requirement reflects the agency's experience that the most important safety problems with a new drug are usually discovered during the first 3 years of marketing. Although this periodic reporting requirement is less frequent than the 30-day time frame that was proposed, FDA believes that the quarterly/annual time frame reflects better than did the proposal the relative importance and relative urgency of the information being reported (i.e., known and nonserious adverse drug experiences). Moreover, the final rule is more stringent in this respect than the current regulations, under which quarterly reporting is required for only 1 year before less frequent reporting is permitted.

The final rule also provides that FDA may extend quarterly reporting requirements beyond 3 years (when warranted by adverse drug experience received to date), may reestablish the quarterly reporting requirements at a later point in time (such as following approval of a major supplement), or may require the applicant to submit reports at other specified intervals. Thus, the regulation provides for increased surveillance of drugs when the circumstances so warrant.

The final rule states that quarterly reports are due within 30 days of the close of the quarter (the first quarter beginning on the date of approval of the application) and that annual reports are due within 60 days of the anniversary date of approval of the application. The time frame for submission of annual reports conforms to other annual reporting requirements under § 314.81

(4) Format for periodic reports. The final rule specifies the content of periodic reports. These reports are designed to perform two functions: (a) Report to FDA the adverse drug experiences not previously reported under the 15-day requirement; and (b) present an overview of all the safety-related information learned during that quarter or year. In order to serve this second function, each periodic report is required to contain a narrative summary and analysis of the information contained in the report and an analysis of the 15-day alert reports submitted during the reporting interval; an index of all adverse drug experiences reported for the first time in the periodic report; and a history of actions taken, if any, since the last report because of adverse drug experiences (e.g., labeling changes or studies initiated). FDA believes that this safety profile overview will improve the agency's ability to spot drug safety trends.

(5) Followup reports. Several comments addressed the issue of followup reports. These comments urged FDA to require followup reports to be submitted 30 days after the date of receipt of followup information, not 30 days after the date of the original report (as had been proposed). One comment proposed 60 working days for submission of complete followup information on 15-day reports. Another comment asked for clarification about appropriate action if followup information cannot be obtained.

Because FDA has substituted quarterly and annual reports for the proposed 30-day reports, the agency expects that followups will be needed principally for the 15-day alert reports for "serious and unexpected" adverse drug experiences. With respect to these, the final rule requires applicants to investigate them promptly. Along the lines suggested by a comment, FDA has revised the final rule to tie the timing for submission of followup reports to the receipt of new information, rather than to the original report. Thirty working days, however, as suggested by the comment, is too long a period, given the possible importance of the information. The final rule, therefore, requires the submission of these followup reports within 15 working days of the receipt of new information or as requested by FDA. If the applicant seeks, but cannot obtain, additional information about an experience, a followup report may be required that briefly describes the steps taken to obtain the information and the reason the new information is unobtainable. Any followup information for adverse drug experiences submitted as part of a periodic report may be submitted with the next periodic report.

Finally, like the proposal, the final rule requires that records of adverse drug experiences be retained by applicants for a 10-year period. The record retention requirement has been moved from the "annual reports" section to the "adverse drug experience" section so that all requirements concerning adverse drug experiences can be found in one place in the regulations.

d. Other options considered. FDA decided on the time frames described above only after consideration of a wide range of options. For example, several comments urged that fatal and life-threatening adverse drug experiences be reported sooner than 15 working days, such as "immediately," within 24 hours, or within 1 week. One comment argued that FDA should require applicants to submit early reports of all fatal and life-threatening adverse drug experiences, instead of only those that are unexpected. At the other end of the spectrum, several comments urged that reporting intervals should not only become less frequent the longer the drug is on the market, but that at some point in time (e.g., 10 years after approval) reporting of known reactions should be eliminated entirely.

In response to these comments, the agency notes that the final rule does provide for reporting of "serious and unexpected" adverse drug experiences "as soon as possible," with 15 working days being the maximum. FDA strongly encourages the promptest possible reporting of these adverse drug experiences. The agency believes, however, that reducing the time for submitting these reports would serve only to increase considerably the number of incomplete reports received by the agency. A large volume of such reports would make it more difficult for FDA to decide on a course of action, and would tend to clog up the system with useless information. FDA's experience is that 15 working days is sufficient time for applicants to gather enough information to submit a meaningful report, even though some followup may still be required. Moreover, the agency believes that adverse drug experiences already described in a drug's approved labeling need not be reported within 15 days even if those experiences were fatal or life-threatening.

The importance of information about such experiences would be limited primarily to the question of whether they occur more frequently than assumed. As discussed above, however, any significant increase in frequency of a serious, expected adverse drug experience is also subject to the 15-day reporting requirement.

With respect to the last comment, FDA has staggered the reporting intervals for known and nonserious adverse drug experiences depending on the length of marketing experience. However, FDA does not believe it would be prudent to eliminate annual reporting across-the-board, even after several years of marketing experience, because of the possibility that long-term or other rare or latent effects might be detected.

72. Definition of adverse drug experience. Several comments objected to the scope of the proposed definition of an adverse drug experience, which built certain examples into the definition itself. One comment suggested that the current, more general definition should be retained. Another comment, finding the proposed definition open-ended, urged that the final definition be specifically limited to the listed examples. A third comment suggested that the agency delete information about drug overdose, drug abuse, and drug withdrawal because such information could more efficiently be obtained from the Drug Abuse Warning Network (DAWN) system, sponsored by the National Institute on Drug Abuse. Finally, one comment suggested that the definition should be evaluated to include drug misuse, which would provide useful information for treating emergencies.

FDA disagrees with these comments. FDA believes that the proposed definition of an adverse drug experience, which is retained in the final rule, improves upon the current definition because the specific examples provide clearer notice to applicants of what is required. FDA also believes that the definition should be left open-ended because public health protection requires the reporting of all adverse drug experiences, even those that do not fit into one of the more common categories. With respect to use of the DAWN system, although FDA uses drug abuse information generated by that system, its inherent limitations limit its usefulness such that it should be viewed as complementary to the adverse drug reporting system, with each contributing to an assessment of the abuse liability of drugs. Finally, the agency does not agree that "drug misuse" should be added to the definition because drug misuse often does not result in an adverse event.

73. Several comments objected to including in the definition of an adverse drug experience any failure of a drug product to produce its expected pharmacological action. Because drug products are not expected to be effective in all patients, these comments urged that only significant or unusual failures be reported, a required by current regulations.

FDA agrees that the final rule should be revised so that, as with the current regulation, only a "significant" failure of a drug to produce its expected pharmacological action would be reportable. While most instances of drug failure would be understood by physicians to represent the usual variances of biological responses, some failures of action are more important, reflecting, for example, a drug interaction or an unresponsive patient subpopulation. Such failures may also indicate manufacturing problems or batch failures. It is these types of failure that are likely to appear in the literature or as reports to the applicant, and the final rule requires that they be submitted to FDA.

74. Tabulation of adverse drug experiences. Several comments contended that a tabulation in the annual report of adverse drug experience reports already reported on Form FDA-1639 is an unnecessary duplication of the other reporting requirements, and would add greatly to the work of applicants without any obvious benefit. One comment suggested that an applicant's tabulation of adverse drug experiences would be less complete and, thus, less useful than FDA's own data base, from which a tabulation could be made.

FDA has revised this section to require that the applicant provide only an index of all adverse drug experiences submitted for the first time in the periodic report. This index is to consist of a line listing of the applicant's patient identification number and adverse reaction term(s). The index is intended to order the potentially large volume of information being submitted and to provide FDA reviewers with ready access to particular reports when necessary.

75. Published literature. Several comments objected to the proposed requirement to transfer information from the published literature onto a Form FDA-1639 and urged, instead, that FDA retain its current rule of simply accepting the published articles themselves. These comments argued that such transfer is an unnecessary clerical exercise that would require major expenditures of time, effort, and money. One comment suggested that even an abstract of the article should be sufficient.

The efficient handling of adverse drug experience reports requires that they be made in a form that is convenient for the agency to process. FDA is currently receiving almost 40,000 adverse drug experience reports annually. To analyze those reports efficiently, the agency has developed a reporting form that reflects FDA's experience in monitoring drug safety in a centralized reporting program. Each item of information on a fully completed Form FDA-1639 (Drug Experience Report) fulfills one of the following four purposes: (1) Recordkeeing information, (2) information necessary to monitor compliance, (3) information relating to the seriousness of the report and the event or reaction, and (4) information relating to the sequential relationship between the drug and the event or reaction. Moreover, as constructed, Form FDA-1639 is also intended to facilitate data entry into FDA's computer base. Given the large number of reports submitted to the agency, and the agency's small staff for reviewing and processing them, FDA's system will work only if applicants transfer reports from the scientific literature to Form FDA-1639's. FDA believes, however, that preparation by the applicant of 1639 forms for literature reports represents a minimal burden because, as described below, the regulations limit the kinds of literature reports that need to be submitted, and because the applicant will necessarily have to review any given literature report to determine if it meets the criteria for reporting. Morever, if the applicant believes that the preparation of a 1639 form represents an undue hardship in any particular instance, the regulations provide that the applicant may arrange with the Division of Drug and Biological Product Experience for an acceptable alternative reporting format.

76. Several comments questioned the need for submitting adverse drug experience reports based on the scientific literature. For example, one comment argued that literature reports often do not contain the information needed to complete FDA's form and, therefore, that this requirement will provide FDA with little useful information. One company estimated that, under the proposed requirement, it would have to copy and submit to FDA almost three 5-drawer filing cabinets of literature articles each year, and that this would amount to over 100 filing cabinets industrywide. According to this comment, the number of additional employees needed by the industry and FDA to copy, submit, and review these articles would also be excessive. Other comments suggested that FDA limit the scope of the published reports falling under this section to, for instance, reports in the published literature "primarily concerned" with the occurrence of adverse drug experiences, or only those relating to fatal or life-threatening experiences. Finally, one comment asked whether the requirement applied to individual experiences reported in letters to a journal.

FDA agrees with those comments that urged FDA, in order to keep the amount of information manageable, to limit the scope of required reports from the scientific literature. FDA has revised the final rule in two ways. First, the final rule limits literature reporting to "serious and unexpected" adverse drug experiences and any "significant increase in frequency" of a serious, expected adverse drug experience (i.e., those subject to the 15-day reporting requirement). By focusing the literature review and reporting on the most important adverse drug experiences, this requirement achieves the objectives of a signaling system while maintaining a reasonable reporting burden on applicants. Reporting of the vast numbers of individual cases of known or nonserious adverse drug experiences recorded in the literature would not materially advance public health protection.

Second, the final rule limits the kind of literature reports subject to the 15-day requirement in the following ways. With respect to reporting "serious and unexpected" adverse drug experiences, the final rule limits literature reporting to adverse drug experiences appearing in scientific and medical journals as "case reports" or as the result of a formal clinical trial. Case reports are reports of experiences in individual patients, including those appearing in letters to the editor and in studies of adverse effects, but do not include literature reports of adverse drug experiences in clinical trials that do not tie experiences to individual patients. The limitation should help provide FDA with complete, rather than partial and less useful, information about events reported. In addition, limiting the requirement to reports in scientific and medical journals ensures that reports come from scientifically credible sources. As noted above, a Form FDA-1639 is required for each case report, even when a journal may contain less than all items of information needed to complete the form. With respect to reporting a "significant increase in frequency," the final rule limits literature reporting to scientific and medical journals containing reports of either formal clinical trials, or epidemiologic studies or analysis of experience in a monitored series of patients. Once again, this limitation is intended to focus attention on those types of literature reports most likely to yield useful information.

77. Several comments said that the proposal is unclear about when FDA considers an applicant to have knowledge of an experience in a published report. Unsure about when FDA will impute to an applicant knowledge of a published report known by one of the applicant's employees, one comment recommended that applicants be required to report only experiences that employees discover in the normal course of business through a literature review program, or that employees discover on their own time (e.g., while reading a scientific journal at home) and bring to their supervisor's attention at work. However, according to this comment, the regulation should not require that applicants establish literature review programs.

As was clear in both the proposal and the final rule, adverse drug experiences an applicant discovers through an organized literature review program must be reported. Although the final regulations do not require applicants to establish literature review programs, an applicant is obligated to report those experiences that come to its attention in the normal course of business. Whether an employee's knowledge of a report in a scientific journal would be imputed to the applicant will depend upon the factors surrounding the employee's knowledge of the report. As a general rule, however, FDA will consider companies responsible for information known to employees, and companies should adopt procedures that require employees to bring important information to the attention of superiors.

78. Several comments suggested that the regulations should permit a single initial Form FDA-1639 for an adverse drug experience in multiple patients from nonliterature sources because the number of patients is often exaggerated. According to these comments, individual forms could be required for followups of documented patients.

FDA believes that permitting the use of a single initial report for multiple patients with individual forms for followup, while it might reduce by a small number of the forms required, has the potential for creating confusion about the number of experiences reported. It is necessary for FDA, if it is to utilize the data properly, that information on the number of adverse events be received in an unambiguous manner so as to reflect clearly the extent of a problem. The submission of multiple events on a single reporting form is inconsistent with the agency objective. Moreover, a practice of grouping reports on one form would make it harder for FDA to determine whether an experience was covered by an initial report and thus was reported in a timely way, and whether appropriate followup was conducted in each case.

79. Identification of patients. Several comments objected to the provision under which FDA would have access to individual patient information. For example, comments suggested that the review of patient records by FDA raises questions about their continued confidentiality. Several comments urged that submission of patient records should require a determination in writing by the Director of the Center for Drugs and Biologics that there is good cause to believe that the reports in the application do not represent actual cases or actual results obtained, or that FDA should provide examples of situations where good cause to review actual reports would exist. Some comments suggested that the proposal did not provide the same types of protection for patient confidentiality accorded by State statutes. These comments suggested that FDA should describe the safeguards the agency will employ to protect and ensure patient privacy.

FDA believes that these comments misunderstood the proposal as it relates to FDA access to patient records. FDA disagrees with the suggestion that its safeguards for information that identifies patients are inadequate. As noted in the proposal, FDA urges applicants not to include names and addresses of individual patients in adverse drug experience reports, although applicants should inlcude some other identifier, such as initials or code numbers. Initials and codes are useful for eliminating duplicate reports of an adverse drug experience. As noted in the regulations, names of patients, health care practitioners, hospitals, and any geographic identifier are not releasable to the public under FDA's public information regulations in Part 20 (21 CFR Part 20). Moreover, FDA's Division of Drug and Biological Product Experience routinely deletes information that could identify patients, health care professionals, and hospitals before copies of adverse drug experience reports are provided to the public, or even to other components within FDA itself. Thus, FDA believes that the final rule adequately protects confidential information about patients.

80. Several comments also believed that the proposal implied that applicants should maintain in their records the names and addresses of patients. One comment stated that its practice is to retain only identifying information that permits it to find the name and address of a patient, using records maintained by the investigator. Another comment noted that an applicant may be unable to obtain the patient's name, as some hospitals will not release patient identification. The comment suggested that the phrase "upon written request by FDA the applicant shall submit individual patient identification information from designated reports" should be changed to "the applicant shall maintain sufficient patient identification information to permit FDA, by using that information alone or along with records maintained by the investigator of a study, to identify the name and address of individual patients."

FDA agrees with this comment and has revised the final rule to provide that an applicant need only retain identifying information that permits FDA to find the name and address of a patient using records maintained by the applicant or maintained by the investigator in a study.

81. Postmarketing clinical trials. Several comments urged that adverse drug experiences from clinical investigations conducted on marketed drugs under an investigational new drug application (IND) should be exempt from the reporting requirements because study blinding will make it impossible to identify whether the adverse drug experience was associated with either the test drug or the control drug. Accordingly, this comment suggested that adverse drug experiences from these studies should be reported to FDA in the final study report. One comment noted that in double-blind studies it is not known whether an experience is associated with a placebo, a control drug, or the study drug, and the code should only be broken for fatal or life-threatening reactions. One comment urged that the regulations clearly specify whether adverse experiences occurring with an approved drug product used in a clinical study under an IND should be reported to the application or the IND. Another comment objected to the use of Form FDA-1639 for reporting experiences from clinical investigations conducted under an IND. According to this comment, those experiences are best reported in the final clinical report, which should be submitted after the study is completed.

FDA agrees with the general thrust of these comments and has revised the final rule to provide that only "serious and unexpected" experiences or a "significant increase in frequency" of a serious, expected experience (i.e., those subject to the 15-day reporting requirement) must be reported when they occur in clinical trials conducted using marketed drugs. As noted above, the 15-day reports are the most important part of the adverse drug experience reporting system, and it is important to keep these reports current. FDA does not interpret this requirement as requiring clinical investigators to break the blinding code, but this requirement does apply to serious, unexpected adverse drug experiences when the code is normally broken anyway (such as when the patient dies or drops out of the study).

82. Several comments also objected to FDA prohibiting the reporting of adverse drug experiences from Phases I and II studies on Form FDA-1639.

The prohibition objected to has been deleted from the final rule. FDA agrees that reporting of "serious and unexpected" adverse drug experiences from clinical trials on marketed drugs required under this section should be submitted on a Form FDA-1639. As noted above, the review of adverse drug experiences by FDA's Division of Drug and Biological Product Experience is geared to this form, and its use also facilitates entry of the information into the computer base for marketed drugs. This interpretation does not apply to 15-day reports of significant increases in frequency which, for reasons described above, are to be reported in narrative form. It should be noted, however, that the final rule does not apply to reporting requirements under the IND regulations (Part 312), where a more detailed type of reporting may be required because much less is known about the safety of unmarketed drugs and, therefore, more extensive information on individual incidents is needed.

83. Postmarketing surveillance/epidemiological studies. One comment objected to the submission of adverse drug experience information from postmarketing surveillance/epidemiological studies on Form FDA-1639 in the same fashion as information from spontaneous reports because these studies would generate a large number of reactions that would overwhelm the spontaneous reporting system. The comment suggested that only unexpected adverse drug experiences from those studies be submitted under the schedule for spontaneous reporting, with other experiences summarized and submitted later.

FDA has revised the final rule in response to this comment. First, FDA recognizes that reports occurring in a structured study must be evaluated separately from spontaneous reports. Thus, the agency asks that reports of adverse drug experiences clearly note when an experience occurred in a postmarketing study. The agency will file these study reports separately from spontaneous reports. Second, as with postmarketing clinical trials, the 15-day reporting requirement will apply to these studies only where there is no blinding or when the blinding code is otherwise broken, and these reports are required to be submitted on Form FDA-1639. However, other adverse drug experiences from these studies will be subject to periodic reporting and will be required to be reported following the completion of the study (a study is considered completed 1 year after it is concluded); applicants are encouraged to submit these adverse drug experiences in a format different from Form-1639, if agreed to in advance by the Division of Drug and Biological Product Experience.

84. Recordkeeping. Several consumers objected to requiring recordkeeping of adverse drug experience reports for only 10 years, arguing that such data may be useful later if a drug is found to have serious adverse effects that do not show up for many years; for example, if the drug is found to be carcinogenic. In contrast, another comment argued that the requirement that adverse drug experience records be maintained for 10 years is excessive, suggesting instead that complete records be retained for 5 years and a summary of adverse drug experiences be retained for an additional 5 years.

FDA has not found it necessary to rely upon applicant records that are more than 10 years old for evaluating current adverse effects, including delayed effects like carcinogenicity. Thus, the agency cannot now justify a record retention requirement of more than 10 years. In addition, FDA would prefer to be able to obtain full rather than summary records when and if needed. The agency is not persuaded that retaining complete records for 5 years and then reducing them to a summary is less burdensome than simply retaining the records for 10 years. Therefore, the final rule will remain as proposed.

85. Miscellaneous issues. On its own initiative, FDA has made several additional modifications to the final rule relating to adverse drug experiences. First, the agency has limited the reporting of adverse experiences from foreign marketing to those considered to be "serious and unexpected" as well as those representing a "significant increase in frequency" of a serious, expected adverse drug experience (i.e., those subject to the 15-day reporting requirement), consistent with other efforts to target FDA resources on the most important adverse experiences.

Second, the final rule, like the current regulations, requires any person (in addition to the applicant) whose name appears on the label of an approved drug product (i.e., a manufacturer, packer, or distributor) to comply with the 15-day reporting provisions on adverse drug experiences. Although FDA proposed to delete this requirement for nonapplicants as part of a broader effort to reduce recordkeeping and reporting requirements generally, FDA believes that the 15-day reporting of adverse drug experiences is sufficiently important, and that it is sufficiently likely that any person whose name is on the approved label will be a recipient of adverse drug experience complaints, that this reporting requirement should be retained. In order to avoid unnecessary duplication of reporting, however, a nonapplicant's obligation under this section may be met by forwarding the adverse drug experience information it receives to the applicant within 3 working days, and by retaining a record of that transmittal.

Third, the agency has continued the current rule of requiring two copies of adverse drug experience reports, rather than the proposal's requirement of only one copy, to expedite review of the reports by the Division of Drug and Biological Product Experience and the Office of Drug Research and Review or the Office of Biologics Research and Review, which both evaluate adverse drug experiences. Because of the large volume of reports received, copying by FDA will unnecessarily delay the review of this important information. The agency believes that spreading this burden among all applicants is both reasonable and efficient. Applicants should send both copies of these reports in the same envelope or package directly to the Division of Drug and Biological Product Experience, and the agency will route the second copy to the Office of Drug Research and Review or the Office of Biologics Research and Review. The final regulation also contains a provision for waiver of the requirement for a second copy (for example, in the quarterly/annual report, the reviewing division may want only the tabular listing of non-15-day reports, rather than full Form FDA-1639's).

Fourth, the final rule contains a caution against the submission of multiple reports for the same adverse drug experience. Thus, an applicant should not include in reports under this section any adverse drug experiences that occurred in clinical trials if they were previously submitted as part of the approved application. If a report applies to a drug for which an applicant holds more than one approved application, the applicant should submit the report to the application that was first approved. If a report refers to more than one drug marketed by an applicant, the applicant should submit the report to the application for the drug listed first in the report.

Finally, FDA has added a provision stating that an adverse drug experience report submitted in accordance with these regulations does not necessarily reflect a conclusion by either the applicant or FDA that the report constitutes an admission that the drug caused or contributed to an adverse effect. This "disclaimer" provision parallels a similar provision recently added to the Medical Device Reporting (MDR) regulation (49 FR 48272; December 12, 1984) in response to comments raised concerning products liability consequences of reporting possible adverse effects. FDA advises, however, as it did in the December 12, 1984 notice, that although FDA does not intend for such a report to be viewed as an admission of liability, whether a court will treat a submission to FDA as an admission will depend on factors outside of the agency's control, such as the contents of the report itself.

FDA believes this disclaimer incorporates long-standing agency policy in the drugs area. Both the previous and the new drug regulations require reporting of adverse events, whether or not considered to be caused by the drug in question. FDA is adding the disclaimer provision for purposes of articulating consistency with the new MDR regulation. For the reasons stated in the December 12, 1984 notice, this provision does not require notice and comment rulemaking and will be made effective along with the other adverse drug experience reporting provisions of this final rule.

86. Several comments suggested that FDA combine the adverse drug experience and annual reporting requirements into a single section of the regulation, because the separate sections in the proposal were confusing and duplicative.

FDA believes that separate sections describing the "adverse drug experience reporting" requirements and the "annual reporting" requirements are helpful because both FDA and some applicants have separate organizational components devoted to each of these areas. For example, in FDA, the adverse drug experience reports are evaluated first by the Division of Drug and Biological Product Experience, whereas the annual reports are reviewed by the Office of Drug Research and Review or the Office of Biologics Research and Review.

Nevertheless, FDA agrees that the proposal did not adequately segregate the requirements applicable to adverse drug experience reports from those relating to the more general records and reports, and, therefore, the agency has made the following changes in the final rule: First, the section relating to the "postmarketing reporting of adverse drug experiences" will include all the regulatory requirements relating to this topic, including the provisions relating to the retention of records and the annual tabulation, both of which were located in the "records and reports" section of the proposal. Second, the reporting requirements for adverse drug experiences have been deleted from the "other postmarketing reports" section (called "records and reports" in the proposal) because they are also found in the section in the final rule on adverse drug experience reporting (the proposal had listed them in both sections).

87. One comment suggested that the agency monitor more closely applicants' compliance with reporting requirements and suggested that the proposal was unclear about who is responsible for submitting reports of adverse drug experiences. The comment also asked how the information is made publicly available.

FDA urges health care professionals to submit adverse drug experience reports to FDA on Form FDA-1639. Many professionals submit reports to manufacturers, however, and many manufacturers routinely review the literature on their products. It is the reports obtained by the manufacturer with which these regulations are concerned. The regulations clearly place the responsibility for submitting those reports to FDA on the manufacturer. With respect to public disclosure, § 20.111(c)(3) of FDA's public information regulations governs how this information is made publicly available.

88. One comment stated that FDA's regulatory impact analysis on the proposal did not adequately discuss the impact of the changes in the adverse drug experience reporting system.

This comment was made in conjunction with an objection to the proposed requirement that all adverse drug experiences be submitted within 30 working days, a change which the comment believed was excessive and did not provided a corresponding public health benefit. Because FDA has modified that aspect of the proposal, the corresponding economic concern with respect to the proposed 30-day provision is moot. However, the final regulatory impact analysis does address the economic aspects of the major changes between the current regulations and the final rule.

89. Two comments suggested that over-the-counter drugs that are subject to approved applications and that are not intended for systemic absorption, like antimicrobial mouthwashes or soaps and antidandruff shampoos, should be exempt from frequent reporting of consumer complaints, like rashes or minor skin irritations, particularly if the manufacturer provides a toll free telephone number on labels.

FDA believes that the changes in the final rule -- to require only "serious and unexpected" adverse drug experiences to be reported quickly -- meets the concerns of the comments.

Other Postmarketing Reports (§ 314.81)

90. NDA -- Field alert report (§ 314.81(b)(1)). Two comments objected to the proposal specifying that certain reports, required under current regulations to be submitted "immediately," be submitted within 3 working days. These reports covered: (i) Information concerning any incident that causes the drug product or its labeling to be mistaken for, or applied to, another article; and (ii) information concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed drug product, or any failure of one or more distributed batches of the drug product to meet the specifications established for it in the application. Two other comments, mistakenly believing that the agency intended to require immediate reporting of a broader category of information than currently required, urged that the current language of the requirement be retained because the comments found it preferable to and clearer than the proposed revision. Other comments suggested that FDA allow reports by telephone with written followup information.

Although the agency has retained the proposed wording regarding the kinds of information that are required to be reported under this section, FDA intends the final rule to require the same kinds of reports submitted under the current regulation. The major change from current practice is to require the report within 3 working days. FDA has also revised the final rule to state that this reporting requirement applies only to distributed drug products and that the report should be made to the FDA district office that is responsible for the facility that is the subject of the report. To help the district offices recognize these submissions quickly, these reports have been designated "NDA -- Field alert reports" in the final rule. Because these reports can lead to preventing potential safety hazards from products already in distribution, the agency emphasizes that the reports are required for both confirmed and unconfirmed problems. Telephone reports will be permitted, with prompt written followup.

91. Annual report (§ 314.81(b)(2)). Several comments stated that the proposal to require an annual report within 30 days of the anniversary date of approval is unnecessarily burdensome, particularly if adverse drug experiences are reported earlier. One comment suggested a due date of 60 days after the anniversary date, and another comment suggested 6 months. Finally, one comment suggested that annual reports should be eliminated after 3 years of marketing because little new information is obtained after that time.

FDA is persuaded that 30 days may be inadequate for an applicant to compile and prepare an annual report. An annual report under the final rule will differ from current annual reports in that it will contain, in addition to what is currently reported, both a summary of new information about the drug and a description of actions the applicant has taken or proposes to take as a result of that information. Thus, to ensure that the summary is clear, concise, and thoughtful, FDA has revised the final rule to require the submission of an annual report 60 days after the anniversary date of the application.

FDA does not agree, however, that annual reports should be eliminated after 3 years. Animal and clinical data may become available long after a drug is first marketed, and the annual reporting requirement is the most effective means for an applicant to provide it to FDA. Moreover, the annual report is necessary for applicants to inform the agency about changes in the application that are not covered by supplements. Thus, FDA relies upon the annual reporting requirement to monitor continuously the safety and quality of approved drugs while they are marketed.

92. Summary (§ 314.81(b)(2)(i)). One comment objected to the requirement for an annual report summary containing a description of the actions an applicant intends to take as a result of new information because, according to this comment, action by an applicant should not wait until the applicant prepares its annual report.

FDA believes that this comment misunderstood the proposal. The final regulations, like the proposal, do not require that an applicant delay action until an annual report is made: instead, the summary is simply required to contain a description of actions the applicant has taken and actions the applicant proposes to take.

93. Distribution data (§ 314.81(b)(2)(ii)). One comment objected to what was perceived as a requirement for a single report of units distributed for domestic and foreign use. According to this comment, the requirement would make it difficult for FDA to estimate the incidence of a drug's adverse effects because applicants usually will have much less information about adverse experiences in foreign countries.

FDA has revised the final rule to state clearly that quantities of a drug product distributed for domestic use and quantities distributed for foreign use should be stated separately.

93a. Chemistry, manufacturing, and controls changes (§ 314.81(b)(2)(iv)). The final rule retains the current requirement for annual reporting of experiences, investigations, studies, or tests involving chemical or physical properties of the drug that may affect the drug's safety or effectiveness. This provision was inadvertently omitted from the proposal.

94. Nonclinical laboratory studies (§ 314.81(b)(2)(v)). Several comments urged that requirements for reporting nonclinical laboratory studies be limited to active ingredients. One comment asked FDA to require applicants to submit routinely published literature about commonly used drug ingredients, such as acetaminophen, codeine, and atropine, rather than to submit them in annual reports on specific drug products. According to this comment, submission of data on the ingredients rather than on individual products would better enable FDA to monitor the drug products adequately. Another comment urged that summaries of published reports be permitted because the reports themselves often contain lengthy reviews of previous literature. Finally, noting that there is no reason to supply FDA with required information it already has, one comment suggested that FDA limit required submissions to "new" toxicological findings in animal and in vitro studies.

The final rule retains the proposed requirement for reporting nonclinical laboratory studies of inactive ingredients, because both active and inactive ingredients can cause safety problems. FDA has also retained the requirement for submitting study results for inclusion in specific applications rather than making a general submission to the agency. This is because each report an ingredient must be separately evaluated with respect to the drug products that contain it. With respect to published literature, the final rule has been revised to require only summaries of published studies, although the applicant will be required to submit a copy of the published study upon request. FDA has retained in the final rule the requirement for full copies of unpublished nonclinical studies. Finally, the final rule, like the proposal, does limit submissions to "new" toxicological findings in animal and in vitro studies.

95. Clinical data (§ 314.81(b)(2)(vi)). One comment objected to the required submission of articles from the scientific literature, rather than simply a bibliography, because the articles are readily available to the agency. Two comments suggested that an applicant should only be required to submit published or unpublished reports that present new and different information that has not been previously submitted, instead of requiring applicants to submit all available reports. One comment suggested a revision of the phrase "review articles, papers, and abstracts in which the drug is used as a research tool," to clarify that papers (as well as abstracts) in which the drugs is used as a research tool should not be reported.

Although FDA has access to the scientific literature, it would impose a significant burden on the agency if its reviewers were required to obtain reprints of literature references. It is properly the responsibility of the applicant to assure that the application is kept current. Since the applicant is expected to monitor the literature for developments relating to its products, it is not, in FDA's opinion, unduly burdensome to require the applicant to copy relevant articles and send them to FDA.

As suggested by two comments, applicants are not required to resubmit information previously submitted. However, the final rule retains the requirement for the submission of information from any new clinical trials (i.e., not previously submitted). Even if such trials do not contain dramatically different information, they often provide new information about, or insights into, the safety or effectiveness of the drug product. Finally, FDA agrees that reports of papers (as well as abstracts) in which the drug is used as a research tool need not be reported, and the agency has revised the final rule to so provide.

96. Status reports (§ 314.81(b)(2)(vii)). One comment contended that status reports for postmarketing studies are unnecessary because FDA will be receiving adverse drug experience data on a timely basis.

FDA believes that this comment misunderstood the proposal. All that is required is a "statement of the current status of any postmarketing studies." This is simply a requirement to advise the agency about which postmarketing studies, if any, are ongoing, and what the status of such studies is, such as how close a study is to completion. Detailed reporting of adverse drug experiences is not required under this section.

Time Frames for Reviewing Applications (§ 314.100)

97. Several comments objected to establishing limits to the application review time and urged that FDA should emphasize the thoroughness and carefulness of its review instead of merely the speed with which approval decisions are made. One comment suggested that it is unlikely that faster approval could be accomplished without compromising the reliability of FDA's safety and effectiveness decisions. These comments were concerned that the 180-day deadline for reviewing applications may place too much pressure on reviewers and thus reduce the quality of the review. Other comments considered the time frames unrealistic, particularly in view of the proposed changes to increase the number of communications and meetings with applicants. Another comment suggested that the agency's time frames for action on applications may create unreasonable expectations, given the restrictions on the agency's personnel and budget resources.

This final rule, like the proposal, is intended to establish efficient procedures, including time frames for review, under which the approval process operates, without reducing the high level of public health protection the approval process now provides. The 180-day review period reflects the statutory requirements that apply to the approval process. FDA believes that improvements in the regulations (such as those relating to the format and content of applications), together with managerial improvements, provide a reasonable basis for concluding that the time frames in the final rule can usually be met.

98. One comment suggested that the agency's two 180-day time limits for reviewing and filing applications (which overlap by 60 days) are confusing. The proposal was unclear, according to this comment, about whether an action letter will issue within 180 days of FDA's receipt or within 180 days of FDA's filing of the application. Another comment urged FDA to adopt a single time frame under which the agency would file the application 30 days from the date of its receipt, thus starting the 180-day clock. Finally, one comment suggested that FDA establish a special deadline for action by the Directors of the Office of Drug Research and Review and the Office of Biologics Research and Review on division recommendations on applications.

Although the agency recognizes that there is a potential for confusion, it believes that its separate time frames for reviewing and filing applications are necessary and are not unduly complicated. The agency suggests that reviewers and applicants should focus on the provision for issuance of an action letter (either an approval, approvable, or not approvable letter) within 180 days of FDA's initial receipt of the application. This is the "review clock" (i.e., the period in which the application will be reviewed) and it is not affected by the date of filing. Thus, moving the deadline for filing from 60 days to 30 days would not have the effect anticipated by the comment: The 180-day review period would be already running when either filing date (30 to 60 days) was reached.

The second 180-day period, or "filing clock," plays an important role in only that small number of cases where the applicant chooses to enter the formal evidentiary hearing process following the agency's refusal to approve its application. The reason for the "filing clock" is legal: section 505 of the act requires FDA, within 180 days of "filing," either to approve the application or to issue a notice of opportunity for hearing. The preparation of a notice of opportunity for hearing is far more time consuming than the preparation of a not approvable letter. Therefore, by placing the date of "filing" 60 days into the review cycle, the agency gives itself 60 days at the end of the normal review cycle (i.e., issuance of an action letter) to prepare a notice of opportunity for hearing if one is necessary. (As noted below, this 60 days includes 10 days for the applicant to respond to the action letter, so FDA's time is really 50 days.)

What this means, therefore, is that applicant should rely on the 180-day "review clock" as the measure of review time regarding their applications. As described above, this provision calls for the completion of FDA's review and issuance of an action letter within 180 days of initial receipt of the application. The filing notice after 60 days serves as a status report to the applicant that the application has been found to be sufficiently complete for review purposes, and does not affect the period in which applicants are notified of the approvability of their applications. Except in those rare cases that may culminate in a formal evidentiary hearing, the 180-day "filing clock" has no practical significance.

FDA has retained the proposed provision that the "clocks" may be extended by mutual agreement or by the submission of a major amendment. Any extension applies equally to both the "review clock" and "filing clock." This change is consistent with comments, discussed elsewhere in this preamble, that advocated increased use of advisory committees. These comments recognized that bringing a matter before an advisory committee could raise a need to extend the review period.

Filing an Application (§ 314.101)

99. FDA received several comments on the proposed provisions concerning filing an application and procedures to be followed when the agency refuses to file an application. Several comments suggested that the regulations should provide for FDA to file the application within the 60-day period instead of on the 60th day after receipt. Several comments objected, as being insufficient, the 10 days provided in the proposal for an applicant to decide whether to request an informal conference on the agency's refusal to file its application. One comment suggested that the agency allow 30 days for a response, with extensions for good cause. Another comment asked whether an applicant needs to resubmit an application that it files over protest and suggested that references to "automatic filing" are inconsistent with the requirement that the applicant initiate a conference to file an application over protest.

FDA does not believe a change in the final rule to provide for filing an application in less than 60 days would have any practical effect. As noted above, an earlier filing date would not affect the deadline for issuance of an action letter, which remains 180 days after initial receipt of the application. Moreover, because FDA's time to prepare a notice of opportunity for a hearing (following a not approvable letter, when requested by the applicant) is to be the same as the time for filing the application, an earlier filing would limit the time, which is already short, for the agency to prepare the requisite notice of opportunity for hearing.

In response to comments, FDA has revised the procedures for filing over protest. Under the final rule, when FDA refuses to file an application, the applicant will have 30 days to decide whether to request an informal conference with agency officials (rather than 10 days, as provided in the proposal). The final rule also priovides that such an informal conference must be held before an application may be filed over protest. However, these changes also necessitate modifications of the "review clock" with respect to applications filed over protest, because an informal conference requested on the 30th day following a refusal to file would leave FDA only 90 days (30 days plus the 60 days before filing) in which both to hold the informal conference and complete the review of the application. Under the final rule, an application which the agency refuses to file will be considered received, for purposes of commencing the 180-day review period, on the date the informal conference is requested. This change is needed to ensure that FDA will have enough time to review any application that is subsequently filed over protest. Moreover, dating receipt from the date the applicant requests an informal conference will result in conferences being held promptly because the review period will already have commenced.

In response to one comment, the agency has modified the final rule to provide that an applicant need not resubmit a copy of the application when it is filed over protest.

FDA agrees with the last comment and has removed the reference to automatic filing of an application. Nevertheless, FDA believes that it is clear from the final rule that FDA will file a complete application in 60 days, and that even an incomplete application can be filed over protest (at a somewhat later point) if the applicant insists.

100. One comment suggested that the provision under which FDA can refuse to file an application that is incomplete should include the following phrase "other than case reports and other information not expressly required under this part." According to the comment, this change would clarify that the provisions in the regulations for the routine submission of less than all case report forms does not conflict with section 505(b)(1) of the act (21 U.S.C. 355(b)(1)), which requires "full reports of investigations."

FDA believes that the additional wording suggested by the comment is unnecessary. The comment erroneously assumes that only submission of all case report forms satisfies the full reports requirements of the statute. As discussed above, however, case report forms are simply one way in which data from a clinical study can be presented. The final rule requires applicants to submit a combination of summaries, analyses, tabulations, and case report forms, with additional case reports available upon request. These materials satisfy the "full reports" requirements of the act, regardless of whether all case reports are submitted.

101. One comment asked for clarification of the provision under which FDA will refuse to file an application if the drug product that is the subject of the submission is already covered by an approved application. The comment suggested that this should prohibit only an applicant who holds an approved application from filing another application for the same product. The comment stated that the provision should not apply to another applicant filing an application for the drug product.

This provision will permit FDA to refuse to review spurious applications. For example, FDA publishes an "Approved Drug Products List" that identifies applicants who hold approved applications, but this list does not identify distributors. Because some State regulatory officials rely upon the list as an index to legal marketers of drugs, distributors may seek applications for products they already distribute in their own names. FDA's review of such an application would require a commitment of resources, but would not affect the marketing status of the drug under Federal law. Distributors that encounter problems with State procurement or other systems keyed to NDA status should resolve those problems by means that do not involve inappropriate and wasteful use of the NDA process.

Communications Between FDA and Applicants (§ 314.102)

102. Several comments agreed with the policies stated in the preamble to the proposal that open communication between FDA and applicants should be fostered and that FDA should promptly communicate with applicants about deficiencies or the need for additional data. These comments, however, urged that these policies be codified in the regulations in order to institutionalize them more formally.

FDA agrees with these comments and, to reflect its commitment to increasing and improving communication between the agency and applicants, has revised the final rule in the following ways. reviewing an application, FDA shall communicate with applicants about scientific, medical, and procedural issues that arise during the review process. Such communication may take the form of telephone conversations, letters, or meetings, whichever is most appropriate to discuss the particular issue at hand. The final rule also requires communications to be appropriately documented, in accordance with § 10.65.

b. The final rule directs FDA reviewers to make every reasonable effort to communicate promptly to applicants easily correctable deficiencies found in an application when those deficiencies are discovered, particularly deficiencies concerning chemistry, manufacturing, and controls issues. The final rule also provides that FDA will inform applicants promptly of its need for more data or information in the application or for technical changes in the application needed to facilitate the agency's review. This policy is designed to permit applicants to correct such readily identified deficiencies relatively early in the review process and to submit an amendment before the review period has elapsed. However, under the final rule, such early communication would not ordinarily apply to major scientific issues, which require consideration of the entire pending application by agency managers as well as the reviewing staff. Instead, these major scientific issues will ordinarily be addressed in an action letter.

c. The final rule contains a new provision for applicants to have an opportunity for an "end-of-review conference" with agency officials. This meeting would be held at the conclusion of FDA's review of an application, as designated by the issuance of an approvable or not approvable letter. The purpose of this type of meeting is to discuss what further steps need to be taken by the applicant before the application can be approved. This meeting will be available on all applications, with priority given to all applications for new chemical entities and major new indications for marketed drugs.

d. The final rule states that FDA will make every effort to grant requests for other meetings that involve important issues and that can be scheduled at mutually convenient times. This policy is designed to facilitate the free exchange of information between FDA and applicants. However, the final rule discourages "drop-in" visits (except for urgent matters, such as to discuss an important new safety issue) in order to minimize disruption of reviewers' work time.

FDA has revised its staff manual guide on communication between FDA and applicants to conform to the provisions of the final rule.

This expanded provision in the final rule embodies FDA's belief that there should be a continuing dialogue between FDA and applicants throughout the IND/NDA process. In the Federal Register of June 9, 1983 (48 FR 26720), FDA proposed revisions to the investigational new drug regulations (IND Rewrite). That proposal encourages all applicants to participate in "end-of-Phase 2" meetings in order to reach an agreement on the overall plan for Phase 3 clinical investigations and the objectives and designs of particular studies. That proposal further encourages applicants to participate in "pre-NDA" meetings in order to ensure that marketing applications present data in a manner suitable for efficient agency review. Moreover, this final rule, as did the proposal, provides for FDA to notify an applicant 60 days after receipt of the application about whether it is acceptable for filing, thus providing early feedback on the application. Finally, the final rule gives applicants a right to an informal meeting approximately 90 days into the review cycle on applications for all new chemical entities and major new indications for marketed drugs. FDA believes that these changes, when seen as a whole, will foster open and timely discussions between reviewers and applicants.

103. FDA also received several comments on the 90-day conference. These comments suggested that FDA extend 90-day conferences to include not only new chemical entities and major new indications, but also all other NDA's and major supplements, such as new dosage forms. In addition, believing the meeting would be held 90 days after filing, which would be 150 days after receipt of the application, one comment suggested that FDA should be prepared to make an intial determination of approvability at the meeting.

FDA has limited the right to a 90-day conference to new chemical entities and major new indications because these are the most complex applications and because the resources needed to extend this right to all drugs are not now available. The agency believes that the provisions described above for presubmission meetings, notice of filing, and early notice of easily correctible deficiencies will in most cases provide adequate feedback to applicants on less complex applications and supplements. However, as noted above, the agency will entertain requests by applicants for other meetings, and so a 90-day meeting could be requested on applications other than those provided in the final rule.

The agency has revised the final rule to clarify that the 90-day meeting will be held approximately 90 days after the agency receives the application (rather than 90 days after filing) and thus 90 days before the agency would be expected to provide an action letter on it. Because the meeting will be held only midway through the review process, FDA will rarely be able to give its views on the ultimate approvability of the application.

Dispute Resolution (§ 314.103)

104. FDA received a number of comments on the issue of dispute resolution. The proposal outlined a new appeals process which the agency implemented at the time of the proposal through a staff manual guide. Several comments suggested that the appeals process is too complex too address minor administrative and procedural disputes which could be resolved more easily and more promptly by an ombudsman. Several comments also felt that the appeals process is inadequate to resolve major scientific and medical policy disputes which, according to these comments, should be referred (as a matter of right) to one of the agency's standing advisory committees.

FDA is committed to resolving disputes with applicants in a prompt, amicable, and equitable way, and it was towards this end that the appeals process referred to above was implemented. In light of these comments, however, together with the agency's newly articulated policy on communication with applicants, FDA has reevaluated the entire issue of dispute resolution and has revised this provision in the final rule in the following ways.

First, FDA agrees with the comments that an ombudsman should be designated to resolve administrative and procedural disputes, and the final rule has been so revised. The role of the ombudsman is to investigate what the facts are and to facilitate a timely and equitable resolution of the issue. Appropriate issues to raise with the ombudsman include resolving difficulties in scheduling meetings, obtaining timely replies to inquiries, and obtaining timely completion of pending reviews. Further details on this procedure are available in a staff manual guide that is publicly available.

Second, upon reevaluation, FDA believes that the recently implemented appeals process is too complex to meet the needs of the NDA review period, and that the same goals can be achieved through alternative means. This conclusion is based in part on the fact that the appeals process was rarely used during its first year, possibly due to the inhibiting effects of the detailed procedure. The appeals process was conceived in response to industry complaints that "stalemates" were often reached with individual reviewers whereby applications could be delayed indefinitely without the involvement of upper lever FDA managers. In addition, applicants appear to perceive FDA as being unreceptive to attempts by applicants to resolve problems informally during the application review process. The new appeals process was designed to meet these concerns by legitimizing access to the system and by requiring automatic review by higher level agency managers. However, FDA believes that other specific provisions of the final rule meet these concerns, and thereby obviate the need for a formal appeals process.

For example, the time frame imposed for review of applications ensures that issues are raised in a timely fashion with upper level managers, including both division directors and the Directors of the Office of Drug Research and Review and the Office of Biologics Research and Review. Moreover, the "ninety-day conference" and "end-of-review conference," described above, provide a timely mechanism for applicants to meet with appropriate agency officials to discuss and resolve, if possible, important issues. For other scientific or medical disputes that arise during the NDA review process, the final rule provides that applicants should first discuss the matter directly with the responsible reviewing officials. If the issue is still unresolved, applicants may request an informal meeting with the appropriate reviewers and supervisors. Ordinarily, such meetings would be held first with the Division Director, then with the Office Director, and finally with the Center Director if the matter is still unresolved. As noted in the provision on communication between FDA and applicants FDA will make every effort to grant requests for meetings that involve important issues and that can be scheduled at mutually convenient times.

FDA recognizes the advantages of utilizing the advice of outside scientific experts in the dispute resolution process, where practical and feasible to do so. The final rule therefore provides that, in requesting a meeting with the agency to resolve a scientific or medical dispute, applicants may suggest that FDA seek the advice of outside experts, in which case FDA may, in its discretion, invite to the meeting one or more of its advisory committee members or other agency consultants, as designated by the agency. The applicant is also free to bring its own consultants. The final rule also provides that, for major scientific and medical policy issues not resolved by informal meetings, FDA may refer the matter to one of its standing advisory committees for its consideration and recommendations. Although this section does not provide the "right" to advisory committee review requested by some comments, FDA does intend to integrate outside experts more fully into the drug approval process. FDA believes that providing applicants a right to advisory committee review for any disputed issue is impractical from the standpoint of the potential number of controversial issues and the relatively infrequent number of advisory committee meetings. Moreover, utilization of outside advisory committees is committed to the discretion of the agency, and not properly delegated to members of the public. Nonetheless, by involving individual advisory committee members or consultants in the dispute resolution process on a more informal basis, FDA believes that the goal of interacting with the scientific community can be achieved without the delays, resources, and scheduling problems associated with full advisory committee involvements. The role of outside experts in the drug approval process is discussed more fully in the next section of this preamble.

In sum, the dispute resolution procedures in the final rule center on utilizing the most appropriate mechanisms -- be it the ombudsman, informal meetings with outside input, or referral to full advisory committees -- to suit the needs of the particular matter under discussion. Thus, the final rule presents a more comprehensive approach to dispute resolution than did the proposal, and FDA believes these procedures will be useful in addressing the full range of issues that arise during the NDA review process.

In the Federal Register of October 19, 1982 (47 FR 46622, 46634), FDA announced that the appeals process would be implemented 30 days after publication, as detailed in a Staff Manual Guide (CDB 4820.5). That Staff Manual Guide extended the applicability of the new appeals process to the IND phase as well. However, in light of the factors discussed above, FDA is reevaluating the utility of that process in the IND phase also. The agency will announce the results of this reevaluation in the IND Rewrite final rule. In the interim, Staff Manual Guide CDB 4820.5 is suspended, pending that reevaluation, and sponsors should utilize the procedures set forth in § 314.103 of this final rule for disputes regarding IND's as well.

Role of Outside Experts

105. FDA received several comments relating to the role of outside experts in the new drug approval process. Several comments expressed disappointment that the proposal did not formally establish a role for outside experts in the routine review of applications. These comments, believing that involving outside experts would add to the credibility and quality of the decisionmaking process, urged that applicants be given a "right" to advisory committee review of any marketing application.

FDA agrees that the utilization of outside experts adds to the quality and credibility of the decisionmaking process, and FDA intends to improve utilization of experts from the scientific community during the new drug approval process. For example, FDA has centralized oversight of its human prescription drug advisory committees by establishing a separate office for this purpose within the Office of the Center Director of the Center for Drugs and Biologics. The agency has also begun, on a more regular basis, to include individual advisory committee members in meetings with applicants to discuss scientific issues. The advisory committee issue was not addressed in the proposal because current regulations were seen as providing the necessary flexibility to accomplish these goals. However, in order to respond to comments, this preamble sets forth FDA's policy in this area.

FDA solicits advice from outside experts who serve as either members of advisory committees or as individual consultants. Fifteen standing public advisory committees provide FDA with advice on human prescription drugs. The committees correspond to the drug review groups in the six new drug evaluation divisions, and operate under charters subject to renewal (or cancellation) every 2 years, as required by the Federal Advisory Committee Act.

These advisory committees are also subject to FDA regulations (21 CFR 14.160-14.174), which provide for the committees to advise the Commissioner "generally" on the safety and effectiveness and regulatory control of human prescription drugs, and "specifically" on any particular matter before the agency, including whether the available information is adequate to support a determination that a particular drug meets the statutory standards for proof of safety and effectiveness necessary for marketing approval. High priority items include drugs subject to active IND's and pending NDA's that offer potential therapeutic advances, that pose significant safety hazards, that present narrow benefit/risk considerations, that have novel delivery systems or formulations, that are the subject of a major scientific or public controversy, or that are the subject of special regulatory requirements, such as a limitation on clinical trials, a patient followup requirement, postmarketing studies, or boxed warnings. In addition, applicants can ask to have any relevant matter brought before a full committee.

Advisory committees are used to bring outside experts into the new drug evaluation process in order to: (1) Supplement FDA's in-house expertise; and (2) help agency staff maintain familiarity with current state-of-the-art technology by fostering a close working relationship between FDA scientists and outside experts actively involved in the field. Advisory committee meetings also serve an important function by providing a public forum for discussion of issues.

Advisory committees review, at FDA request, certain critical studies or critical elements of studies on drug products under consideration and labeling issues. They respond to specific questions posed by the agency to identify the adequate and well-controlled studies which demonstrate effectiveness, the seriousness of certain adverse effects, and whether additional studies or data are necessary before a decision can be reached.

FDA also seeks outside advice on clinical research issues. For example, FDA developed approximately 25 clinical guidelines with the help of its advisory committees and others, including the American Academy of Pediatrics' Committee on Drugs and consultants to the Pharmaceutical Manufacturers Association. The guidelines contain generally accepted principles for reaching valid conclusions about the safety and effectiveness of drugs, and they contain views of recognized experts about appropriate methods for studying specific classes of drugs.

Individual advisory committee members have also become involved in the IND process by attending the "end-of-Phase 2" conference, where they aid in the planning of Phase 3 studies. This involvement is explicitly recognized in the IND Rewrite proposal (48 FR 26732).

In addition to advisory committee members, FDA also employs representatives from the scientific community as special consultants or expert reviewers. These persons are called upon for advice on technical matters on an ad hoc basis, or are asked to undertake special review assignments in areas where the agency staff may lack particular expertise or available resources. These consultants may also be present at advisory committee meetings.

In summary, FDA believes that the primary goal of the advisory committee (and outside consultant) system should be to help the agency make sound decisions based upon the reasoned application of good science, and the IND/NDA Rewrites reflect this goal. As noted earlier, the IND proposal provides for the inclusion of outside experts in "end-of-Phase 2" conferences during which the design of the major Phase 3 studies is planned. In addition, as described in the preceding section of this preamble, this final rule envisions the participation of outside experts in informal meetings to resolve scientific and medical disputes, and provides for the referral by FDA, if necessary, of major disputes to a full advisory committee.

The principal and perhaps only issue on which the agency disagrees with the comments is whether applicants should be permitted to utilize advisory committees on demand to review applications or resolve scientific disputes. FDA believes that only the agency is in a position to decide the relative importance of which issues advisory committees should consider. Whether to refer a particular marketing application or scientific dispute to an advisory committee is partly a resource issue given the limitations on time and scheduling that restrict the use of advisory committees, and partly a matter of judgment, based on whether FDA decides that the committee is needed to supplement the agency's internal expertise in evaluating the type of data under review. FDA believes strongly, however, that areas of legitimate scientific debate greatly benefit from the broader views that can be provided by an outside advisory committee, and that committee participation significantly enhances the scientific credibility of any decisions reached. Accordingly, FDA intends to make full use of its advisory committees to ensure that this result is achieved. As noted above, it is agency policy to include, as a priority for advisory committee review, marketing applications where the approval decision is a "close call," from either a safety or efficacy standpoint. This policy, together with an applicant's ability to request advisory committee review under § 14.172, should provide applicants adequate access to advisory committees while still allowing the agency to set reasonable priorities.

106. A number of comments addrressed the subject of conflict of interest. Several comments believed that current conflict-of-interest barriers prevent FDA from using many qualified outside experts and recommended that (1) FDA issue clear guidelines to resolve conflict-of-interest problems; (2) the Commissioner waive conflict of interest rules more often where a closer examination of the facts would show that the expert will be able to serve in an unbiased manner; and (3) FDA solicit a less restrictive interpretation of Federal conflict-of-interest statutes and regulations from the Department of Justice. Other comments expressed concern about FDA'a outside experts and asked for assurance that such advisors will be free of conflicts of interest.

FDA's procedures for employing outside experts appear in staff manual guides and in materials provided to outside experts who are employed to advise the agency. These procedures are designed to ensure that advisors' private interests do not conflict with their public responsibilities. Thus, FDA's guidelines with respect to conflict-of-interest issues are quite clear and widely disseminated. Where highly qualified persons are not free from nongovernmental or private financial interests that present a conflict or potential conflict, FDA may appoint those individuals to serve on a particular committee but exclude them from participation in certain specific matters in which a real or potential conflict of interest exists. In addition, the Commissioner may waive FDA's conflict-of-interest rules in those instances where FDA is persuaded that an outside expert can, despite a conflict of interest, make an impartial and essential contribution to FDA's mission and strict application of the rules would frustrate the best interests of the public. Because of the high level of interest on this issue, however, FDA is reviewing its conflict-of-interest rules to ensure that a proper balance is struck between obtaining advice from those experts most knowledgeable in the field and ensuring that such advice is free from potential bias.

Approval of an Application (§ 314.105)

107. FDA received several comments concerning the proposed policy, stated in the preamble, that the agency would approve an application based on draft labeling if the only deficiencies found in the labeling were editiorial or otherwise minor in nature. Two comments suggested that FDA codify this policy in the final rule. Another comment suggested that FDA should not approve an application on the basis of draft labeling, because of the importance of labeling during the introduction of a product into the market and the possibility that final printed labeling would not conform exactly to the approved draft labeling. One comment asked how the agency intends to determine whether appropriate changes have been made in final printed labeling after the agency has approved an application on the condition that deficiencies in draft labeling are corrected before marketing.

FDA has concluded that it should approve an application before submission of final labeling if the agency determines that only editorial or similar minor deficiencies exist in the draft labeling, and the final rule has been so revised. This change in practice should expedite drug approvals without compromising the safety or efficacy of drugs. As described elsewhere in this preamble, when FDA anticipates approving an application based on draft labeling, the agency will request a final safety update report under § 314.50(d)(5)(vii)(b) to ensure that the approval is based on the most up-to-date safety information available. When an application is approved under this provision, the approval letter will detail the specific changes required in the labeling and state that approval of the application is conditioned upon incorporating those changes exactly as directed. The approval letter will also require applicants to submit to FDA a copy of the final printed labeling prior to marketing. Although applicants will not have to wait for prior approval of the final printed labeling, this procedure will enable FDA to ensure that the final labeling conforms to the conditions of the approval.

108. One comment urged that FDA revise the final rule to state that approval of an application not be dependent upon the availability of the summary basis of approval.

FDA disagrees with this comment. An SBA is prepared for all original applications and supplemental applications for a new use or a substantially different dosage. The SBA is prepared by the supervisory medical officer (group leader) within the reviewing division and becomes part of the final approval recommendation forwarded to the Division Director and the Director of the Office of Research and Review or the Office of Biologics Research and Review. Because FDA supervisors may rely, in part, upon the SBA in determining whether to approve a drug, the agency believes that the SBA needs to be prepared before an application is approved. FDA notes, however, that approval of the application may be based on a draft SBA and precede completion of the final version of that document.

109. One comment, who agreed that FDA must exercise flexibility when applying approval standards to different kinds of drugs, argued that FDA must be even handed when applying the standards within a class of drugs.

FDA agrees generally that applications for similar drugs should be handled in the same manner. Nevertheless, applications for new members of an established class of drugs should take into account experience gained with that class, as FDA will take such information into account in making approval decisions. This may involve, for example, more detailed safety data if marketing experience with the class has revealed special safety concerns.

Foreign Data (§ 314.106)

110. FDA received a number of comments on the proposed provision setting forth conditions for approving an application based solely on foreign data. In the past, FDA's policy has been, with rare exceptions, to require some U.S. data (in the form of adequate and well-controlled studies) before approving a new drug for marketing. Nevertheless, while requiring the inclusion of U.S. data in applications, FDA has also relied increasingly upon foreign data in its approval decisions, consistent with the increasing quality and quantity of research performed in other countries. Based upon this experience with foreign data, the agency, like the medical community in general, has come to recognize the very high quality of drug testing that has emerged from a number of foreign research institutions.

The proposal built on this experience and sought to balance the ability to place increased reliance on foreign data with appropriate safeguard designed to ensure the quality of those data. The proposal removed the "presumption" in current policy that U.S. data would be required and replaced this with the principle that FDA's foremost consideration would be the quality of the data submitted, regardless of the country of origin. Thus, the proposal presupposed that some foreign studies are of comparable quality to U.S. data such that repeating the studies in this country would be neither scientifically necessary nor in the public interest.

At the same time, however, the proposal recognized that foreign data do present three unique problems not associated with domestic data. These involve (1) medical, genetic, and cultural differences between countries; (2) lack of FDA's familiarity with many foreign clinical investigators and facilities; and (3) FDA's inability to conduct on-site verification of many foreign studies. To meet these concerns, the proposal specified that three criteria must be met before the agency could approve a new drug based solely on foreign data. These three criteria were (1) that the foreign data were applicable to the U.S. population and U.S. medical practice; (2) that the studies had been performed by clinical investigators of recognized competence; and (3) that the data could be considered valid without the need for an on-site inspection by FDA or, if FDA considered such an inspection to be necessary, that FDA would be able to validate the data through on-site inspection or other appropriate means.

Thus, the proposal was cast so as to convey both a more open attitude on the part of FDA to consider the merits of foreign data in their own right, but also to safeguard the public health by imposing rigorous criteria that must be met before approval based on those data could be granted. In this way, the proposal sought to focus attention on the scientific merit of the data rather than on unnecessarily rigid rules regarding domestic data requirements.

111. The major concern raised by comments was the possibility that FDA's proposed policy could result in lower quality drugs being approved based on foreign studies. For example, one comment suggested that foreign studies may not meet U.S. standards because foreign research is less concerned with peer review and institutional review boards, features less vigorous controls and lower reporting of adverse drug experiences, and, unlike studies in this country, is not publicly reviewed in the current U.S. medical literature. Several comments believed that the policy should be drafted more narrowly so as to apply only to major medical breakthroughs. Opponents of the foreign data policy also cited the recommendation of the Commission on the Federal Drug Approval Process that suggested that some U.S. clincial experience be required before approving a new drug in this country.

FDA has reviewed these comments in detail, but has concluded that the arguments raised do not warrant any change in the proposed regulation. The essence of the comments was a concern that the three safeguards would be insufficient to ensure the quality of drugs approved solely on the basis of foreign data. FDA does not believe that this concern is valid. The criteria contained in the regulation are rigorous, and the agency intends to apply them with the utmost regard for the public health. The rationale for these criteria is discussed at length in the preamble to the proposed regulation (47 FR 46643-46644; October 19, 1982). The agency believes that if the foreign data are applicable to the U.S. population and U.S. medical practice, if the studies are performed by recognized, competent investigators, and if there are no concerns over the validity of the data, then there is no justifiable public health reason not to approve the drug on the basis of the data. In this regard, the agency notes that comments did not suggest inclusion of additional safeguards that, in their minds, would ensure the quality of a drug based solely on foreign data.

As noted in the preamble to the proposed regulations, the agency does agree with comments that the nature of the drug should be taken into account in applying this policy, and that drugs representing major medical breakthroughs would be among those at the upper end of the spectrum. Other drugs falling into this category would be those for diseases that are uncommon in the United States (e.g., tropical diseases and orphan drugs), and drugs on which decisionmaking is less difficult from a risk-benefit point of view (e.g., topical products). However, the agency does not believe that the policy should be applied exclusively to these types of drugs; rather, any drug meeting the criteria should be included.

Finally, FDA does not agree with the recommendation of the Commission on the Federal Drug Approval Process that at least some U.S. experience with a drug be required before it is approved for marketing in this country. Under the Commission's recommendation, such U.S. experience could be in the form of uncontrolled trials where clinicians administer the drug to patients in settings closely resembling normal clinical practice. The agency believes that the Commission's emphasis on uncontrolled trials in this context is misplaced. First, as described above, FDA believes that the three criteria in the regulation adequately ensure the safety and effectiveness of new drugs prior to marketing and that, in those situations, uncontrolled trials would not add significantly to the body of data supporting approval. Second, when the regulation's criteria are not met, FDA does not believe that the mere inclusion of U.S. experience in the form of an uncontrolled trial would be sufficient to meet the test for marketing approval. (See 47 FR 46644.)

112. Several comments supported FDA's proposal to accept foreign data as the sole basis for approval of an application because it recognizes the international nature of clinical research and brings FDA into line with other countries that accept data based exclusively on scientific merit. Some comments, however, suggested that because FDA has inadequate resources and funding to monitor the validity of foreign research and to make on-site inspections, FDA should require more extensive documentation of foreign studies than of domestic studies, including the submission of all case report forms from each foreign study.

FDA agrees that foreign studies forming the sole basis for approval may require more extensive documentation than domestic studies, but the agency believes that the regulations are already flexible enough to accommodate this need. As discussed elsewhere in this preamble, the provisions for submission of summaries, analyses, data tabulations, and certain case report forms should be adequate for FDA's initial review of foreign clinical studies, and FDA will have additional access to data and information, including case report forms, if these are needed. In addition, as noted above, FDA may request full case reports from the most critical studies, and this would include foreign studies as well.

113. Several comments argued generally that the proposed policy was too restrictive. The only specific comments on this point concerned FDA's intention to consider the international reputation, publication experience, participation in meetings, and other factors relating to the competence of foreign investigators. One comment found these tests to be inappropriate, arguing that they are not applied to domestic investigators. Another comment that agreed with the standards urged that FDA establish a mechanism for collecting biographical information to assess the competence of foreign investigators so that individual applicants did not have to.

As noted above, FDA believes that the regulation's three criteria, including the requirement for the clinical investigators to be of recognized competence, are necessary to safeguard the safety and effectiveness of any drugs so approved. Although the review of clinical investigators' competence is highlighted in the foreign data policy, that review is not unique to foreign studies. FDA reviews the qualifications of all clinical investigators, but such a review is more easily conducted with respect to domestic investigators because FDA is generally familiar with them and their institutions. Indeed, FDA has refused to rely on data compiled by domestic investigators who are found to be unreliable. A review of the competence of foreign investigators is therefore also necessary, and FDA believes it appropriate to require the applicant to submit the necessary documentation. FDA believes that this approach will be more practical and efficient than relying on an FDA-compiled biographical library of foreign clinical investigators, which may be incomplete, out-of-date, or otherwise insufficient.

114. Two comments objected to the foreign data policy because it may encourage applicants to conduct more testing abroad. According to these comments, such "export of testing" would have adverse consequences for the United States both economically and scientifically.

Although FDA recognizes there is some merit in the concerns raised by these comments, the agency does not believe it justifiable to impose domestic testing requirements solely for trade restriction purposes, particularly when such requirements might produce an adverse effect on the public health through the delay of approval of new drugs. Moreover, FDA believes that there are two factors mitigating against the concerns raised by these comments. First, in the IND Rewrite, the agency has proposed to give sponsors greater freedom to conduct the early phases of clinical research, in part due to complaints that U.S. regulatory requirements are too strict and are causing U.S. companies to conduct more and more research abroad. Thus, the purported incentive for moving research abroad is being addressed. Second, as discussed in the preamble to the NDA Rewrite proposal, the agency believes that even with the new foreign data policy, most applications will continue to contain some U.S. data. This is due, in part, to the high quality of U.S. clinical investigators as well as to the view that having some domestic physicians familiar with a new drug once it is approved enhances its prospects in the marketplace.

115.-116. One comment asked that FDA hold a presubmission meeting at which an applicant can present to FDA its proposal to rely upon foreign data. Another comment suggested that the agency's appeals process should be available to applicants if FDA refuses to accept foreign data, and that FDA should raise issues regarding the quality or acceptability of foreign data before the relevant standing advisory committee. The final regulation, like the proposal, specifically encourages applicants to meet with the agency to discuss their plans to submit applications that rely solely upon foreign data. It should be understood, however, that the adequacy of the data cannot always be assessed prior to a detailed review, and the review can occur only after the application is submitted. The dispute resolution procedures described in the final rule would be applicable to foreign data issues, and this would include referral of those issues, at FDA's option, to an advisory committee.

117. Several comments argued that FDA should be required to accept foreign data unless the agency can demonstrate that the data should not be accepted for some valid scientific or medical reason. These comments also urged that the final rule require FDA to explain in writing its refusal to accept foreign data to ensure that duplicative domestic studies would not be required except for good reason.

FDA disagrees with these comments to the extent that they suggest that the burden of proof should be on the agency to show why foreign data are inadequate. Rather, the final rule, like the proposal, places the burden on the applicant to demonstrate to the agency's satisfaction that the foreign data are sufficient, by themselves, for approval. The agency emphasizes that there are no hidden criteria for evaluating the acceptability of foreign data. FDA will approve an application that relies upon foreign data unless one of the grounds identified in the statute or regulations for refusing to approve an application applies. If the agency concludes that the application is not approvable, it will give the applicant the basis for the conclusion in a deficiency letter or a not approvable letter and, if the applicant wishes, in a notice of opportunity for hearing. Thus, a mechanism already exists under which FDA will explain to the applicant, in writing, its reasons for refusing to approve an application based solely on foreign data.

Approvable and Not Approvable Letters (§ § 314.110 and 314.120)

118. One comment understood an approvable letter to mean that, except for matters specifically identified in it, the information already submitted in the application is acceptable and will not be further reviewed, and, except for safety update reports, no more information will be required before approval. Another comment suggested that an applicant's unconditional agreement to comply with conditions in an approvable letter should be sufficient for the agency to approve the application immediately, and that no extension of the review period or additional submission should be needed.

FDA agrees that an approvable letter means that FDA, at the time the letter issues, intends to approve the application if the applicant submits the requested data or information. Nevertheless, the issuance of an approvable letter does not preclude FDA from reexamining any part of the application in light of the applicant's response to the letter, or any other data or information before the agency bearing on the application. Although applicants have long argued that FDA should not re-review parts of an application that it has once determined are acceptable (and FDA agrees that in most cases another review is unwarranted), the agency considers all parts of an application to market a new drug to be interrelated, so that a change in one part may affect other parts of the application. Thus, FDA will continue to consider the impact of new submissions on other sections of the application. With respect to the second comment, except in the situation where the only changes to be made are editorial or affect minor aspects of the draft labeling, FDA believes that responses to approvable letters must be reviewed by FDA prior to final approval of the application because the information submitted could affect the safety or effectiveness of the drug.

119. Several comments argued that 10 days is inadequate time for an applicant to respond to an approvable or not approvable letter and that an applicant should have at least 30 days from the date of receipt of the letter, with an opportunity for extensions of time for good cause. According to these comments, in many cases the applicant must gather a number of experts in several disciplines together to consider FDA's letter, recommend a course of action to management, and obtain a management decision on it.

FDA does not believe that the 10-day period for a response to an approvable or not approvable letter will necessarily be insufficient for applicants to determine whether they will seek to amend an application, or request that the agency issue a notice of opportunity for hearing. In some cases, applicants may have enough information regarding the status of their applications prior to receipt of the action letter to know whether anticipated deficiencies are amenable to remedial action by the firm, or whether they are so great as to require pursuit of an administrative hearing. More importantly, however, the primary purpose in revising this section of the regulations was to provide for agency action within the 180-day time frame specified by the act. In meeting its obligations to reach a decision within the statutory period, the agency has undertaken to observe strict time limits in the review of new drug applications. As meeting the statutory period will necessitate industry responses to agency action, reasonably strict time limits are appropriately applied to industry as well.

Nonetheless, the agency recognizes that in many cases applicants may find 10 days inadequate to respond to an approvable or not approvable letter. For example, the applicant may wish to delay such a decision until after it has had an opportunity to meet with FDA officials in an "end-of-review conference," as provided in § 314.102(d). Thus, FDA has amended the regulations to permit applicants to respond by agreeing to an extension of the approval time, as provided under section 505(c) of the act. Moreover, the regulation makes clear that FDA will honor any reasonable request for such an extension. The 10-day provision, therefore, should not create any undue hardship on applicants. This resolution of the issue presented by the comments accommodates both the comments' concern and the agency's need to adhere to the 180-day period provided for by statute. The agency considered shortening the time necessary to prepare a notice of opportunity for hearing to accommodate a longer period for an applicant's response to an action letter, but has determined that it is impracticable to shorten the period in which a notice of opportunity for hearing can be prepared to less than 50 days.

120. Several comments objected to the automatic 45-day extension of the review period when an applicant decides to file an amendment in response to an approvable letter. Two comments suggested a provision permitting extensions of "up to" 45 days, while two other comments suggested that 30 days is appropriate. Another comment suggested that the agency should advise the applicant in writing about what the time will be, but that it should be no more than 45 days. FDA selected 45 days as the maximum time for FDA action on the applicant's response to an approvable letter because it believes it will generally take that long to review the applicant's response, prepare an approval letter recommendation, and issue the approval. If that process is completed sooner, the approval letter will issue in less than 45 days. The agency believes, however, that a significant number of applications would fail to meet the 30-day time period suggested by the comments and, thus, the agency has not adopted it. In addition, FDA believes that the requested change would distract reviews from evaluating the submission by requiring them to decide on a feasible extension shorter than 45 days, and thus would be more likely to disrupt the review process than to benefit applicants.

Refusal To Approve an Application (§ 314.125)

121. Noting that the first six reasons for refusing to approve an application rephrase the statutory grounds in section 505(d) of the act, one comment argued that the agency failed to assert a legal basis for the remaining eight reasons and that, accordingly, those eight reasons should be deleted.

FDA does not agree. The agency views each of the grounds stated to be within the scope of section 505(d) of the act. Each of the grounds asserted, both those stated explicitly in section 505(d) of the act and those not, reflect FDA's authority to prohibit marketing of drug products that do not comply with regulatory standards that marketed drugs be safe, effective, and properly labeled. FDA would view as unreasonable a requirement that, for a ground not specifically listed in section 505(d) of the act but included in § 314.125, it must approve such a product and immediately take action against it under some other section of the act. Rather, FDA views it as a reasonable exercise of its rulemaking authority to include within the reasons for refusing to approve an application under section 505(d) of the act reasons consistent with the agency's authority to establish marketing requirements for, or withdraw approval of, new drugs. Moreover, FDA believes that the list of additional grounds in the regulations will give applicants more specific notice of the kinds of grounds on which the agency will refuse to approve applications.

122. One comment objected to FDA removing the characteristics of an adequate and well-controlled study from this part of the current regulation, fearing that it suggested a predisposition of FDA not to involve qualified experts in the evaluation of clinical investigations to determine whether substantial evidence of effectiveness exists.

FDA disagrees and concludes that changing the location in the regulation of the provision in question will have no substantive effect on the agency's refusal to approve an application for a lack of substantial evidence of effectiveness, nor will it affect the role of experts in the review process. The regulation retains almost verbatim the grounds cited in the act for refusal to approve an application because of a lack of substantial evidence of effectiveness. The discussion of the characteristics of adequate and well-controlled studies, although placed in a separate section and somewhat revised in language, is still comprehensive in nature and can be cited by the agency in any decision not to approve an application.

123. One comment urged FDA to exempt minor deviations in proposed labeling when determining whether it complies with the requirements for labels and labeling in 21 CFR Part 201. Other comments objected to the suggestion that bioavailability or bioequivalence data are intended to show that a drug is safe or effective, while one comment asked FDA to retain the wording from the current rule under which approval may be refused if the data in the application do not meet the requirements in 21 CFR Part 320. One comment stated that it is unnecessary to include the provision for refusal to approve an application if a deficiency noted in a refusal-to-file letter had not been corrected. Finally, one comment objected to FDA's assertion that it can refuse to approve an application if the applicant does not permit an FDA investigator to inspect the facilities, controls, and any records relevant to the application. The comment contended that that provision goes well beyond FDA's inspectional authority in section 704(a) of the act (21 U.S.C. 374(a)).

Although FDA has reaffirmed its policy to approve an application if editorial or similar minor changes in draft labeling will be made in the final printed labeling, FDA cannot sanction deviations from the standards in Part 201 that would cause the drug to be misbranded. The agency agrees that the current wording under which FDA may refuse to approve an application if bioavailability and bioequivalence data do not meet the requirements in Part 320 is more informative than the proposed wording and the agency has revised the regulation to retain it. Because an applicant can file an incomplete application over protest, FDA sees a need to retain the provision permitting the agency to refuse to approve an incomplete application. Finally, FDA is obligated to refuse to approve an application if it believes (in the absence of an inspection that would demonstrate otherwise) that the facilities and controls are inadequate or the information in the application based on records helds by the applicant is insufficient to determine that the drug is safe or effective. An inspection under this provision derives from section 505 of the act and the result of an inspection refusal is the possibility that the agency will not have adequate information to approve the application. The agency notes that although it has suggested it would refuse to consider a particular study if records of the study could not be inspected, it does not take the position that it will reject an entire application solely because a part of the records could not be inspected (so long as they were not considered essential to the approval).

Adequate and Well-Controlled Studies (§ 314.126)

124. Several comments objected to FDA's statement that the characteristics set forth in its regulations are recognized by the scientific community as the "essentials" of an adequate and well-controlled study. Comments suggested that the listed characteristics do not uniquely define such a study. A study may, according to comments, include an additional characteristic or lack one or more of the listed characteristics and still be adequate and well-controlled. For example, one comment suggested that the characteristics of an adequate and well-controlled study should include an explanation of the difference between the study's objectives and its results so that deviations from the original objectives can be justified, while other comments urged that the characteristics should not include the method of selection of subjects, the method of assigning subjects to treatment groups, the measures taken to minimize bias on the part of analysts of the data, the method of assessment of subjects' responses, or an assessment of a study's ability to detect more than a "clinically significant" difference between treatments. Another comment suggested that study characteristics should appear in a guideline instead of a regulation. That change, according to the comment, would recognize that appropriate alternative characteristics exist, and would provide clinical investigators and sponsors with flexibility to adopt them without first obtaining a waiver.

FDA has long considered the characteristics listed in the regulation as the essentials of an adequate and well-controlled study, and the proposal modified these characteristics only slightly. In general, the regulation on adequate and well-controlled studies has two overall objectives: (1) To allow the agency to assess methods for minimizing bias; and (2) to assure a sufficiently detailed description of the study to allow scientific assessment and interpretation of it. Many of the characteristics identified in the regulation are relevant to the second objective (rather than the first, as implied by the comments) and are needed by the agency to conduct a proper review of the study. Thus, FDA is not persuaded that these types of changes in the regulation are now warranted. The agency emphasizes, however, that it applies the regulation with judgment, not as a check-list. A scientifically acceptable study is not rejected because of minor technical deficiencies if it is apparent that the study is basically sound. Moreover, the regulation permits applicants to seek a waiver of individual requirements with respect to investigations.

125. Several comments were concerned that the agency's reordering of the types of controls that may be applied in a study was intended to establish a preferential order for the types of studies supporting an application. One comment said that because the proposal listed placebo concurrent control first, it implied that such a study is preferred over, for instance, a study using a historical control that was listed last. Several comments objected to this implied preferential order of studies because it would encourage researchers to adopt one type of study over another based on FDA's views, instead of considerations about the treatment of patients. These comments recommended that the final rule should clearly state that no study method is preferred over another.

Although the final rule lists the types of controlled studies in a different order than in the current regulation, the reordering does not mean that FDA considers one type of control to be necessarily preferred over another. The reordering is intended simply to reflect FDA's experience that some types of studies (e.g., placebo-controlled studies) are often easier to interpret than other kinds of studies (e.g., those using a historical control). Thus, FDA has listed the types of controls in descending order roughly in accordance with the ease of interpretation. (For this reason, the dose-comparison concurrent control has been moved to second on this list, rather than fourth.) FDA recognizes, however, that ethical and practical considerations will play a central role in the type of study selected, a decision that will ordinarily depend upon the type and seriousness of the disease being treated, availability of alternative therapies, and the nature of the drug and the patient population. In each case, applicants must choose the particular type of study they will use based on ethical, scientific, and practical reasons. So long as these judgments are justifiable, and the studies are properly designed, the approvability of an application will not be affected. Thus, the regulation lists five different kinds of controls that are acceptable; it does not state a perference for one kind over another.

126. Two comments suggested that the final rule distinguished between therapeutic and diagnostic new drugs in determining the appropriate features of an adequate and well-controlled study of the drug. For example, according to thes comments, a placebo concurrent control study would neve be indicated for diagnostic products, such as radiopharmaceutical and contrast media that are intended to have no physiological or therapeutic effect. One comment suggested that current regulations be modified to recognized more clearly this distinction.

FDA agrees that there are good reasons for using different study designs in particular situations, and the agency believes that the regulation is sufficiently flexible to accommodate the needs of applicants in this respect. As a matter of past practice, the agency has approved products whose safety and effectiveness were established using each of the controls listed in the regulation. However, because of the many situations involved, the agency believes it is neither necessary nor feasible to describe them specifically in the regulation.

127. One comment urged that the standard for obtaining a waiver from the adequate and well-controlled study criteria should be changed to require a statement of why a particular criterion need not be applied to the particular clinical investigation "in view of other factors," instead of a statement of why the criteria are not "reasonably applicable."

FDA disagrees with the comment and has retained the current wording in the final rule. The act states that adequate and well-controlled studies are needed to demonstrate the effectiveness of drug products. The agency's regulation describing the characteristics of adequate and well-controlled studies, which is modified only slightly in this final rule, has served satisfactorily as a basis for approvals over time and, as discussed above, contains the essential elements of such studies. Thus FDA concludes that a narrow waiver provision that requires well-justified bases for an exemption should be retained.

128. FDA has, on its own initiative, made the following changes in the final rule describing adequate and well-controlled studies.

First, FDA proposed to delete the current requirement that the method of analysis be included in the plan or protocol of a study. The rationale for this proposed change was that, although having the method of analysis in the plan or protocol has been listed as a characteristic of an adequate and well-controlled study, many protocols, especially those developed years ago, lacked this characteristic. While FDA does not believe the omission of this information means a study is not well-controlled, there is no doubt that the development of a tentative plan for analysis: (a) Minimizes the potential for analyst bias; and (b) helps focus attention on whether it is practical to collect the data and whether variables to be obtained are analyzable. Accordingly, the final rule encourages inclusion of such a plan for analysis in the protocol but permits, as an alternative, the study report to include a description of how the analysis was selected.

Second, at a number of points the regulation has been modified to address potential problems associated with multiple or interim data analyses. These do not render a study less than well-controlled, but they must be described and reflected in the analysis.

Finally, FDA has modified the description of the active treatment concurrent control. This is because a demonstration of effectiveness by means of showing similarity of the test drug to an active control is an indirect demonstration of effectiveness (the active control treatment serving as an intermediary in a comparison between the test drug and placebo). Under this study design, similarity of test drug and active control drug can mean either that both drugs were effective or that neither was effective. Thus, the agency has added a requirement that the analysis of the study provide an explanation of why the active control drug should be considered to have been effective in the completed study, for example, by reference to results in previous placebo-controlled studies of the active control drug.

Withdrawal of Approval of an Application (§ 314.150)

129. One comment suggested that the final rule provide that if FDA found a study to be adequate and well-controlled when it approved the application, that conclusion should remain unchanged even if FDA later adopted new standards under which the study would not be considered adequate and well-controlled. The conclusion would thus preclude withdrawal of the drug's approval upon the basis of new information and an FDA determination that there is a lack of substantial evidence from adequate and well-controlled investigations that the drug is effective.

FDA disagrees with the comment. The factors leading to a determination of what is an adequate and well-controlled study, which is the basis for determining drug efficacy, may, as the comment recognizes, evolve. FDA has an obligation to judge a drug's effectiveness by contemporary scientific standards. If those standards change to the extent that it is questionable whether a drug can be regarded as having been shown to be effective, FDA may under the act appropriately review the drug's status.

Adulteration and Misbranding of an Approved Drug (§ 314.170)

130. One comment supported FDA's proposed clarification of the relationship between the new drug and antibiotic approval provisions of the act and the adulteration and misbranding provisions. In contrast, several comments urged that this section be deleted, believing that the only lawful procedure for dealing with adulterated or misbranded approved new drugs is by withdrawal of approval of the application.

FDA has retained this provision in the final rule. The comments that opposed it submitted no persuasive argument that FDA is incorrect in its position that the new drug provisions do not insulate approved drugs and antibiotics from the general adulteration and misbranding provisions of the act. As FDA has previously noted, the statutory scheme contemplates FDA's application of the adulteration and misbranding standards to all drugs, irrespective of whether those drugs have been subject to the premarket approval requirements of the act.

Hearing Procedures for New Drugs (Subpart D)

131. FDA agrees with one comment that objected to a change in the hearing procedure to remove the requirement that the Director of the Center for Drugs and Biologics serve a proposed order to, and provide for a response from, a person who submits required data or information and requests a hearing following a general or specific notice of an opportunity for hearing. The final rule retains the current requirement.

Administrative Procedures For Antibiotics (Subpart E)

132. One comment suggested that the procedure for issuing antibiotic regulations should be revised to make it as consistent as possible with the approval procedure for new drugs and to expedite the petitioning, rulemaking, and hearing process required under section 507(f) of the act (21 U.S.C. 357(f)) when FDA refuses to approve a new antibiotic.

FDA believes it has already taken adequate steps to conform the administrative procedures that apply to refusals to approve (or withdrawals of approval of) antibiotics and new drugs. The procedures for withdrawing approval of an NDA apply to approved antibiotics (which are now all exempt from certification requirements under § 433.1 (21 CFR 433.1)). A full discussion of the regulatory process applicable to antibiotic drugs maybe found in the final rule exempting antibiotic drugs from certification (47 FR 39155; September 7, 1982) and in the proposed rule preceding that action (47 FR 19954; May 7, 1982). Because the potential exists for a manufacturer to apply voluntarily for batch certification of an antibiotic drug or for FDA to revoke the exemption from batch certification requirements granted to a drug, this final rule retains those provisions necessary for certification of an antibiotic drug, if necessary. In the case of refusals to approve an antibiotic application, while the statutorily based regulatory scheme for the publication of monographs has been retained, the procedures preceding the refusal to approve are, as a practical matter, the same as those employed in a refusal to approve a nonantibiotic application.

Miscellaneous Provisions

133. Imports § 314.410(a). Although several comments supported the agency's proposal to permit an individual to bring into the United States a reasonable quantity of an unapproved drug product that is intended only for personal use, several comments argued that the proposal was illegal and would expand illegal trade in unapproved drugs in this country. These comments were especially concerned about what they believed would constitute FDA's sanctioning of the commercialization of drugs generally regarded by the medical community as being useless. One comment suggested that legislation would be needed to make this change. Another comment suggested that FDA would find it difficult to monitor and regulate this exemption.

The proposal was intended to state the agency's discretionary enforcement policy that it can apply to accommodate the health needs of individuals entering the United States with personal supplies of unapproved drugs. Upon reevaluation, however, FDA finds that policy related to enforcement discretion is better stated in a compliance policy guide. Accordingly, this provision has been deleted from the final rule.

134. Exports (§ 314.410(b)). One comment suggested that FDA seek legislative changes to permit the export of new drug substances and products under the same conditions that apply to the export of antibiotics. Others suggested that, even without legislation, FDA could permit the export of unapproved drug products and of bulk substances which are not covered by an approved application for a drug product. Another comment stated that the current restrictions on exports of unapproved new drugs discourage the manufacture of human drugs in the United States before approval for marketing in this country. According to this comment, because U.S. approval often occurs after foreign approval, these restrictions require that foreign facilities be built to supply foreign markets, resulting in a significant loss of domestic jobs.

Although FDA recognizes the practical impact of current restrictions on the export of unapproved new drug products and bulk new drug substances, FDA believes that it is obligated to reject the comments recommending changes in the final rule. The definition of "interstate commerce" in section 201(b)(1) of the act (21 U.S.C. 321(b)(1)), when read together with the prohibitions on interstate shipment of unapproved new drugs in sections 301(d) and 505(a) (21 U.S.C. 331(d) and 355(a)), prohibit the exportation of an unapproved new drug. Section 801(d) of the act (21 U.S.C. 381(d)), which grants an exemption from the adulteration and misbranding sections of the act for export purposes, does not grant a similar exemption from the new drug provisions. Therefore, FDA has interpreted the act as reflecting a Congressional intent that unapproved new drugs not be exported, though it has, in the past, supported modification of the statutory export provisions (see, for example, proposed section 135 of the Drug Regulation Reform Act of 1978).

Although FDA recognizes the practical impact of current restrictions on the export of unapproved new drug products and bulk new drug substances, FDA believes that it is obligated to reject the comments recommending changes in the final rule. The definition of "interstate commerce" in section 201(b)(1) of the act (21 U.S.C. 321(b)(1)), when read together with the prohibitions on interstate shipment of unapproved new drugs in sections 301(d) and 505(a) (21 U.S.C. 331(d) and 355(a)), prohibit the exportation of an unapproved new drug. Section 801(d) of the act (21 U.S.C. 381(d)), which grants an exemption from the adulteration and misbranding sections of the act for export purposes, does not grant a similar exemption from the new drug provisions. Therefore, FDA has interpreted the act as reflecting a Congressional intent that unapproved new drugs not be exported, though it has, in the past, supported modification of the statutory export provisions (see, for example, proposed section 135 of the Drug Regulation Reform Act of 1978).

Because FDA believes the first comment misunderstood this provision, the agency has revised the final rule to clarify it. The statutory scheme provides that a new drug substance can be exported only if it is the subject of an approved application. Through this new regulation, FDA is interpreting the application approval to extend to a supplier of a new drug substance under that approved application. Currently, only the applicant who holds the approved application may export the drug substance that is used in the manufacture of the approved drug product, whether or not the applicant is itself the manufacturer of the drug substance. The final rule extends to the person (and only to that person or persons) who is identified in an approved application as the source of the drug substance, but is not itself the applicant, permission to export the drug substance, if the substance meets the specifications in the approved application. Thus, FDA will consider the supplier to be covered by the application both when it ships the drug substance to the applicant and when it exports it. Domestic shipment to a party not the applicant, however, will not be permitted.

FDA does not believe this regulatory change will present the safety concerns raised by the comment because FDA will have already conducted a thorough examination of the drug substance, either in the original application or in a supplement.

However, because the drug substance manufacturer's opportunity to export the substance is dependent upon its inclusion in an approved application, it is also dependent on the applicant's continued inclusion as a supplier in its application. The applicant is always free to supplement its application to change suppliers. Such action, under the final rule, would also have the effect of terminating the former supplier's export rights. Moreover, because no approval has been provided to suppliers under the act, FDA does not view the hearing requirement of section 505 of the act to apply to a drug substance supplier who is so terminated by an applicant.

In response to the second comment, FDA does not agree that the filing of a drug master file should be sufficient to acquire a right to export a drug substance. FDA does not review a drug master file except in the context of the agency's review of an application or supplement that references it. Thus, the submission of a drug master file does not now result in any agency action. FDA does not intend to revise this practice by reviewing drug master files independently. Resource constraints on FDA and the lack of a drug product and proper labeling by which to measure the suitability of the drug substance for any purpose warrant maintaining the current practice. Finally, FDA has revised § 201.122(a) to clarify that a drug substance may be exported under the labeling exemption provided by that section, if it is covered by an approved application.

136. Drug master files (§ 314.420). Several comments objected to the proposed requirement that a drug master file holder notify each person authorized to refer to information if the holder adds, changes, or deletes the information. Some comments stated that drug master file holders generally give umbrella authorization to others for use of their master files and that the regulations are unclear about how specific a notification must be made to persons authorized to reference information when the holder adds, changes, or deletes information in the file. Thus, according to these comments, the provision is unnecessarily burdensome and could result in the unwarranted disclosure of trade secrets.

FDA has retained the provision in the final rule. FDA believes that applications that depend upon information in drug master files may quickly become outdated if the drug master file holder does not notify the persons authorized to reference the file about changes in the information in it. Because FDA reviews the contents of a drug master file only in the context of its review of an application or a supplement to an application, a change in important information in a drug master file that may affect the safety and effectiveness of a drug product is not likely to be reviewed unless the owner of the master file notifies the applicant who, in turn, submits a supplement to incorporate the change in its approved application. Recognizing that one of the primary functions of the drug master file system is to maintain the confidentiality of trade secret information, FDA agrees that a file holder's notification about changes in the file does not have to be so specific that the confidentiality of information in the file is compromised.

137. One comment asked whether the requirement that the drug master file contain a complete list of persons currently authorized to reference it can be met by individual letters whenever a person is authorized or an authorization is revoked.

FDA notes that some drug master files are voluminous and subject to substantial amendments over time. Thus, it may be impossible to determine from individual letters submitted at different times the person who is currently authorized to reference a file. For that reason, FDA believes that a single list of persons currently authorized to reference the file should be maintained.